This invention relates to processes for making 3-methylthiophene-2-carboxaldehyde which comprise Michael reaction of a dialkyl acetal of 2-mercaptoacetaldehyde or 2-mercaptoacetaldehyde itself or its equivalent with (1) methyl vinyl ketone or an alpha- or beta-oxidized derivative of methyl vinyl ketone to form a 3-oxobutylmercaptoacetaldehyde or a dialkyl acetal thereof which is then converted to 3-methylthiophene-2-carboxaldehyde via appropriate steps including treatment with acid, followed, if necessary, by enamine catalyzed cyclization and, in the case of using methyl vinyl ketone as reactant, a dehydrogenation step; or (2) 3-butyne-2-one to produce a mixture of isomeric 3-oxobut-1-enylmercaptoacetaldehyde or dialkyl acetals thereof which is cyclized to 3-methylthiophene-2-carboxaldehyde, an intermediate for the syntheses of anthelmintic agents.
A further aspect of this invention is an improved, one-pot process for making dialkyl acetals of 2-mercaptoacetaldehyde, useful as intermediates for a variety of valuable products including various thioethers and 3-methylthiophene-2-carboxaldehyde.
Prior art methods for making 3-methylthiophene-2-carboxaldehyde produce a mixture of said compound and the isomeric 4-methylthiohene-2-carboxaldehyde and/or poor yields of the desired 3-isomer. The production of isomeric mixtures necessitates, for many purposes, a separation of said isomers. This, of course, results in reduced yield of the desired 3-methyl isomer and an increase in cost thereof.
Direct formylation of 3-methylthiophene using (1) formaldehyde and ammonium chloride is reported by Hartough, "Thiophene and Its Derivatives", Interscience Publishers Inc., 1952, p. 510, to give an 11% yield of formylation product in which the ratio of 3- to 4-methylthiophene-2-carboxaldehyde was 99:1; (2) N,N-dimethylformamide and phosphorous oxychloride is reported by Campaigne et al., J. Am. Chem. Soc. 75, 989-991 (1953) to afford a 41% yield of formylation product in which the ratio of 3-isomer to 4-isomer was 78:22.
Still further, King et al., J. Org. Chem., 13, 635 (1948) describe production of an 85% yield of formylation product comprising a 78:22 ratio of 3- to 4-methyl thiophene-2-carboxaldehyde by direct formylation of 3-methylthiophene using phosphorous oxychloride and N-methylformanilide. Direct formylation processes are also described in U.S. Pat. No. 2,853,493, issued Sept. 23, 1958. Gronowitz et al., Arkiv. Kemie 17, 165-77 (1961) describe preparation of 3-methylthiophene-2-carboxaldehyde by reaction of 3-methyl-2-thienyl magnesium bromide with N,N-dimethylformamide. British Pat. No. 1,176,312 published Jan. 1, 1970 describes preparation of 3-methylthiophene-2-carboxaldehyde containing a small proportion of its 4-isomer by reaction of 3-methylthiophene and dichloromethyl methyl ether in the presence of a Friedel-Crafts catalyst.
Tilak et al., Tetrahedron Letters No. 24, 1609-1612 (1964) report a general method for preparation of 2-carboethoxythiophenes which comprises condensation of ethyl mercaptoacetate with an alpha,beta-unsaturated ketone to form a 2-carboethoxy-3-hydroxy-3-methyltetrahydrothiophene which is then dehydrated to a dihydrothiophene using polyphosphoric acid. Dehydrogenation of said dihydrothiophene by means of diphenyl disulfide or chloranil produces the corresponding 2-carboethoxy-3-methylthiophene. Hydrolysis and decarboxylation afford a 3-methylthiophene.
Preparation of 2-methyl-5-isopropenyl-1-cyclopentene-1-carboxaldehyde by an enamine directed aldol condensation is reported by Wolinsky et al. in J. Org. Chem. 29, 3740-3742 (1964).
The use of activated manganese dioxide as a dehydrogenating agent is reviewed by Fatiadi in Synthesis, March 1976, pages 133-136. Minster et al., J. Org. Chem. 43, 1624-6 (1978) and 44, 497-501 (1979) report on the use of nickel peroxide as oxidant for partially reduced heterocycle compounds.
Parham et al., J. Am. Chem. Soc., 75, 2065-2069 (1953) report the preparation of dimethyl mercaptoacetal. Japanese Pat. No. 5328, published July 30, 1955, describes the preparation of bis(2-alkoxyethyl)disulfides by reaction of vinyl alkyl ethers with monochlorosulfide.
Several processes for making 2-mercaptoacetaldehyde dimethylacetal (I, R.sub.1 .dbd.R.sub.2 .dbd.CH.sub.3) are reported by Parham et al., J. Am. Chem. Soc. 75, 2065-2069 (1953). These processes involve reaction of 2-chloroacetaldehyde dimethyl acetal with (1) benzylmercaptan sodium salt to produce benzyl-(1,1-dimethoxy ethyl)sulfide which was then reduced with sodium/ammonia to the desired acetal; (2) sodium sulfide to form 1,1,1',1'-tetramethoxyethyl disulfide followed by reduction of said disulfide using sodium/ammonia or lithium aluminum hydride; and (3) sodium polysulfide to give a mixture of polysulfides which was reduced with sodium/ammonia. A fourth process described in said reference comprises the action of potassium hydrosulfide on diethyl or dimethyl bromoacetal to produce the corresponding dialkyl mercaptoacetal.
The reaction of mercaptoacetaldehyde and 1,4-dithian-2,5-diol, its dimer, with nitriles such as cyanoacetic acid to produce 2-aminothiophene derivatives are described by Gewald, Angew. Chem. 73, 114 (1961) and Robba, et al., Bull Soc. Chim. Fr. 12, Pt. 2, 2864-70 (1974), respectively. German Offenlegungsschrift No. 2,808,321 (C.A. 90, 7591k, 1979) reports the reaction of 1,4-naphthoquinone with the dimer to produce 2-[(formylmethyl)thio]-1,4-naphthoquinone which was cyclized in sulfuric acid to 4,9-dihydronaphtho[2,3-b]thiophen-4,9-dione. Hesse et al., Chem. Ber. 85, 924-32 (1952) report that in solution an equilibrium exits between mercaptoacetaldehyde and its dimer.
The processes of this invention, in contrast to the prior art methods for making 3-methylthiophene-2-carboxaldehyde, afford the isomerically pure product by procedures which are easily carried out and which afford satisfactory yields of product.